Alpha-1 antitrypsin (SERPINA1) E342K mutant allele (SERPINA1 E342K)

The SERPINA1 E342K mutant allele, commonly known as the PiZ allele, is the primary genetic cause of severe Alpha-1 Antitrypsin Deficiency (AATD). This single nucleotide polymorphism (G>A) results in a glutamic acid to lysine substitution at position 342, leading to the misfolding and polymerization of the alpha-1 antitrypsin (AAT) protein within the endoplasmic reticulum of hepatocytes. This process causes a dual pathology: liver injury due to the toxic accumulation of protein polymers and lung disease (emphysema) due to the lack of circulating AAT to protect lung tissue from proteolytic enzymes like neutrophil elastase. Targeting the mutant allele in hepatocyte genomic DNA using gene editing technologies, such as base editing or CRISPR/Cas9, aims to permanently correct the mutation. This approach is designed to restore the secretion of functional, monomeric AAT into the bloodstream while simultaneously halting the production of hepatotoxic polymers.

Other names

PiZ alleleZ mutationSERPINA1 Z variantrs28929474Alpha-1 antitrypsin Z allele

Direct correction of the G-to-A point mutation at the genomic level using base editing or gene replacement to restore production of functional alpha-1 antitrypsin and reduce toxic polymer accumulation.